Abstract

Objective: To assess the efficacy, safety, and tolerability of ropinirole in the treatment of patients with restless legs syndrome.

Methods: A 12 week, prospective, double blind, randomised comparison involving 284 patients from 10 European countries. All participants
had a score of ⩾15 on the international restless legs scale (IRLS). Patients were randomised (1:1) to receive either ropinirole
0.25–4.0 mg once daily or placebo. The primary efficacy end point was mean change from baseline to week 12 in total IRLS score.
Global improvements (clinical global impression (CGI) scale) and improvements in sleep, health related quality of life (QoL;
using generic and disease specific measures), work, and other activities were also assessed.

Restless legs syndrome is a distressing sensorimotor disorder characterised by an urge to move the legs, and accompanied by
sensations deep in the limbs that are variously described as twitching, pulling, and sometimes painful. These symptoms present
at rest, particularly in the evening and at night, and are alleviated by movement. Sufferers commonly report considerable
difficulty in getting to sleep and staying asleep as a result of these sensations. Additional distress, however, is often
caused by periodic leg movements, the primary motor symptoms of restless legs syndrome. Periodic leg movements are described
as rhythmic extensions of the big toe and foot, sometimes with flexions of the knee or hip. These can also cause sufferers
to waken during the night and have difficulty returning to sleep. The profound sleep disturbance resulting from restless legs
syndrome symptoms may contribute to the impaired cognitive functioning and quality of life (QoL) reported in these patients
compared with population norms.12

Current estimates suggest that 5–10% of the adult population suffer from restless legs syndrome.3–5 However, it seems that a smaller proportion, essentially those with moderate to severe symptoms, seeks medical treatment.
As the condition is not commonly recognised or is misdiagnosed, patients receive either no treatment or drugs to alleviate
the secondary symptoms, particularly those relating to sleep. Where the disorder is correctly diagnosed, benzodiazepines and
other sedative drugs have often been used in the past, but these have now been largely superseded by dopaminergic agents as
the treatment of choice. The latter are very effective in restless legs syndrome, which suggests a central role for the dopaminergic
system in the pathophysiology of the disorder.

Among the dopaminergic agents, the efficacy of L-dopa (with a peripheral decarboxylase inhibitor) has been established67 but it is associated with a high incidence of long term side effects involving increased symptom severity (that is, augmentation).8 Preliminary data suggest that the dopamine agonists offer an important alternative in this regard, as augmentation rates
are reported to be substantially lower.9–11 To date, the most rigorous assessment of dopamine agonists has been with pergolide. However, while this particular agent
alleviates symptoms,1213 there are important safety and tolerability concerns associated with ergot derived dopamine agonists generally, even at the
low doses employed for the treatment of restless legs syndrome.14 Small or open label studies with two non-ergoline agonists, ropinirole and pramipexole, have yielded promising results15–18 and large, double blind, controlled trials are now needed to confirm these preliminary findings.

The present study is the first large, international, randomised, double blind, placebo controlled trial to examine the efficacy,
safety, tolerability, and patient reported outcomes of ropinirole in the treatment of restless legs syndrome. Additional work,
focusing specifically on periodic leg movements, will be reported separately.

METHODS

Participants

Men and women aged 18 to 79 years and diagnosed as having restless legs syndrome (using the International Restless Legs Syndrome
Study Group (IRLSSG) diagnostic criteria19) were included in the study. Patients had a score of at least 15 on the international restless legs scale (IRLS)20 and had either experienced at least 15 nights with symptoms of restless legs syndrome in the previous month or, if receiving
treatment, reported they had had symptoms of this frequency before treatment.

Patients were excluded if they were suffering from other movement or primary sleep disorders, if they required treatment for
restless legs syndrome during the daytime (defined as 10.00 to 18.00 hours), if they were experiencing augmentation or end
of dose rebound, or if they had restless legs syndrome associated with end stage renal disease, iron deficiency anaemia, or
pregnancy. Patients were also excluded if they had a history of alcohol or drug abuse, had previous intolerance to dopamine
agonists, or were suffering from other clinically relevant conditions affecting assessments.

Patients gave written, informed consent before entering the study, which was done according to the principles of the 1996
amendment of the Declaration of Helsinki and approved by local ethics committees.

Study design

This was a double blind, randomised, placebo controlled trial of 12 weeks’ duration. It was conducted in 43 hospitals, sleep
centres, and neurology clinics in 10 European countries (Austria, Belgium, France, Germany, Italy, Netherlands, Norway, Spain,
Sweden, and the United Kingdom).

Patients receiving treatment known to affect restless legs syndrome or sleep, or to cause drowsiness, entered a washout phase
equal to either five half lives of the drug or seven consecutive nights, whichever was the greater. A small proportion of
patients may have had a washout period shorter than seven days before the implementation of the protocol amendment.

Patients were randomly assigned in a 1:1 ratio to receive ropinirole or placebo for 12 weeks. To ensure balance in the number
of patients assigned to each treatment group, the allocation schedule was generated in blocks using the sponsor’s coding memo
system. Investigators phoned into the randomisation and medication ordering system (RAMOS) to register and randomise each
patient. Investigators, patients, and study monitors were blinded to the treatment status of the patients at all times. Investigators
and the study sponsor held sealed envelopes containing patient code breaks (comprising the container number and the treatment
allocation). In an emergency, an investigator could have scratched the disclosure panel with a coin to reveal details of a
patient’s treatment. All envelopes were returned unopened to the sponsor at the end of the study.

Interventions

Ropinirole and matched placebo tablets were used to maintain study blinding. Patients received treatment once daily between
one and three hours before bedtime and started ropinirole treatment at 0.25 mg/day. The dose was then titrated upwards during
weeks 1 to 7, through seven predetermined dose levels, until patients were receiving the maximum dose (4.0 mg/day) or they
were judged to have reached their optimal dose. A maximum of two dose reductions because of adverse events (by one dose level
in each case) was permitted during the titration period. The dose could be increased again if adverse events ameliorated.
Dose changes were not permitted after week 7.

Assessments and outcome measures

Patients visited the clinic at baseline, on day 2, weekly for the first two months, and then at week 12.

The primary end point was the mean change from baseline to week 12 in the IRLS total score. This scale was developed and validated
by the IRLSSG20 and comprises 10 questions about restless legs syndrome symptoms and their impact on daily activities and mood. All the responses
are graded in the range 0 to 4 (0 = absence of a problem, 4 = very severe problem), giving a maximum score of 40 (table 1).

The international restless legs scale for severity developed and validated by the International Restless Legs Syndrome Study
Group20

The clinical global impression–global improvement (CGI-I) scale was used to assess general improvements. Changes in the proportions
of patients with scores of “much improved” or “very much improved” on this scale at weeks 1 and 12, and the mean change in
the IRLS total score between baseline and week 1, were identified as the three key secondary end points.

Other secondary end points, concerning the impact of treatment on sleep (sleep adequacy, quantity, disturbance, and daytime
somnolence), health related quality of life, work, and other activities, were measured using four patient reported questionnaires:
the medical outcomes study (MOS) sleep scale, the MOS 36 item short form health survey (SF-36), the RLS QoL questionnaire,
and the work productivity and activity impairment (WPAI) questionnaire.

Statistical analyses

The intention to treat (ITT) dataset was used for all efficacy analyses; this comprised all patients who received at least
one dose of double blind drug treatment and had at least one valid post-baseline efficacy assessment. Safety and tolerability
data were reported for all patients who received at least one dose of the study drug. For this study, the ITT and safety populations
were identical. For all end points, when data were missing, the value from the previous visit was carried forwards (except
for the IRLS total score at day 2, which represented an inadequate recall period from baseline and was not carried forward
to estimate week 1 or week 12 results).

Continuous efficacy variables were assessed using analyses of covariance, dichotomous variables using logistic regression,
and “time to event” data with Cox’s regression model. Baseline score (with the exception of CGI-I), country group, and treatment
were fitted as terms in the model. Statistical modelling assumptions were assessed and not found to be violated.

For the primary end point, a sample size of 116 patients per group was necessary to ensure 90% power to detect a difference
of six points between groups with an SD of 14 (α = 0.05, two tailed test).

RESULTS

Patient characteristics and flow through the study

The study was carried out between 8 November 2001 and 19 August 2002. In all, 286 patients were randomised and 284 received
treatment (146 ropinirole, 138 placebo; the ITT population). Similar numbers of patients completed the study in the two groups
(fig 1). Patient characteristics at entry were also similar in the two groups (table 2).

Treatment

Efficacy results

Primary end point

The mean (SD) IRLS total score at week 12 was lower in the ropinirole group (13.5 (9.3) points) than with the placebo group
(17.1 (9.4) points). The adjusted mean (SE) improvement in the IRLS total score at week 12 was significantly greater for ropinirole
(−11.04 (0.719) points) than for placebo (−8.03 (0.738) points; adjusted treatment difference = −3.01 (95% confidence interval
(CI), −5.03 to −0.99)) (p = 0.0036).

Key secondary endpoints

Significantly more patients in the ropinirole group (53.4%, 78/146) showed a “much improved” or “very much improved” score
on the CGI-I scale at week 12 compared with the placebo group (40.9%, 56/137; adjusted odds ratio = 1.7 (1.02 to 2.69)) (p = 0.0416).

Treatment differences in favour of ropinirole were apparent by the first assessment—that is, at week 1. The mean (SE) reduction
in the IRLS total score from baseline was significantly greater for ropinirole (−8.19 (0.59) points) than for placebo at week
1 (−5.14 (0.62) points; adjusted treatment difference = −3.05 (−4.72 to −1.38)) (p = 0.0004). Similarly, significantly more
patients in the ropinirole group (34.2%; 50/146) had a score of “much improved” or “very much improved” on the CGI-I scale
compared with the placebo group at week 1 (13.1%; 18/137; adjusted odds ratio = 3.7 (2.02 to 6.94)) (p<0.0001).

Other secondary end points

There were significant differences in favour of ropinirole for the median time taken to show a decrease of at least six points
on the IRLS total score and the median time taken to report a score of “much improved” or “very much improved” on the CGI-I
scale (figs 2 and 3).

Kaplan–Meier plot of median time to report a score of “much improved” or “very much improved” on the clinical global impression
global improvement scale.

The ropinirole group experienced significantly greater mean improvements in sleep adequacy and quantity (p = 0.0015 and p = 0.0331,
respectively), and greater mean reductions in daytime somnolence and sleep disturbance (p = 0.0064 and p = 0.0245) compared
with the placebo group (fig 4). Furthermore, ropinirole was also associated with a greater mean improvement in quality of
life as assessed with the disease specific measure, the RLS QoL questionnaire (17.1 v 12.6, respectively) (p = 0.0314). There were no differences between groups, however, in the changes on the generic measures,
the SF-36 and the WPAI questionnaire.

Safety results

The most commonly reported adverse events were nausea and headache; nausea was more common with ropinirole than with placebo
(table 3). Most events were mild to moderate in intensity (table 3). The frequency of adverse events declined over time in
both groups: after day 70, only 9.6% (14 patients) in the ropinirole group and 5.8% (eight patients) in the placebo group
reported new adverse events. There were no reports of augmentation.

Few patients withdrew because of adverse events (16 with ropinirole v 6 with placebo). Nausea led to most withdrawals in the ropinirole group (6, v 0 with placebo), and restless legs symptoms in the placebo group (3, v 0 with ropinirole). Serious adverse events were also unusual (3 with ropinirole v 4 with placebo) and none led to withdrawal or was judged to be related to the study drug (menstrual disorder; injury; gastrointestinal
disorder; urinary tract infection; fever, syncope and pharyngitis; fever; abdominal pain).

DISCUSSION

Ropinirole, at single doses of up to 4.0 mg/day, was significantly more effective than placebo in alleviating symptoms of
restless legs syndrome, improving sleep quantity and adequacy, reducing sleep disturbance and daytime somnolence, and improving
health related quality of life. Importantly, the superiority of ropinirole was apparent as early as week 1. Furthermore, ropinirole
was generally well tolerated and there were no reports of augmentation or sudden onset of sleep.

This is the largest controlled trial in restless legs syndrome conducted to date and it employs a validated scale,20 the IRLS, to determine the impact of treatment on the severity of the condition. As there has been limited experience with
the IRLS as a tool for monitoring treatment response, the CGI-I was also employed, and these data confirm the clinical relevance
of the IRLS results. Furthermore, in the key area of sleep disruption, which is troublesome to a very large proportion of
patients with restless legs syndrome, ropinirole was significantly superior to placebo on all of the variables tested. The
reduction in daytime somnolence has particular importance as it indicates that ropinirole is not acting as a sedative. This
is further supported by the fact that similar proportions of patients in each group reported somnolence (not necessarily daytime somnolence) as an adverse event (12% of patients in the ropinirole arm and 7% in the placebo arm).

The positive results in this trial are consistent with the efficacy findings from small short term studies in which ropinirole
doses of up to 6.0 mg/day were associated with significant improvements in symptoms1517 and benefits were apparent within one day.1821 An early onset of action is clearly an important factor influencing the choice of treatment.

The adverse event profile of ropinirole in the present study is typical of those associated with dopaminergic treatment generally.
The rates of withdrawal because of nausea and vomiting were, however, rather low (5%).

Ropinirole was effective despite the presence of a placebo effect that was larger than expected. Such effects are common in
trials in other disease areas in which subjective tools are used to assess efficacy (for example, migraine and depression).
Furthermore, restless legs syndrome is generally poorly recognised,22 and the receipt of a long awaited diagnosis, coupled with individual attention from physicians, may have enhanced the patients’
expectations of treatment. In support of this, patients receiving placebo experienced a greater number of dose increments,
with 45% reaching the maximum “dose” compared with 16% in the ropinirole group.

Ropinirole is an effective and well tolerated treatment for restless legs syndrome. Follow up studies are required, however,
to confirm that efficacy and the lack of augmentation are maintained in the longer term and to explore whether improved sleep
among patients treated with ropinirole will be associated with improved cognitive functioning. Data from additional work examining
the efficacy of ropinirole on periodic leg movements and further sleep measures are expected soon.

Acknowledgments

Footnotes

↵* A full list of the members of the TREAT RLS 1 Study Group is given in the appendix.

Competing interests: PT has received sponsorship from GSK and other pharmaceutical companies marketing dopamine agonists to
attend international meetings, and has been an investigator in clinical trials of dopamine agonists in Parkinson’s disease.
CT has received honoraria for educational lectures and consultancy fees from GSK, Eli Lilly, and Boehringer Ingelheim. No
other authors have any disclosures to make.